rs33954691

chr5-1255405-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198253.3(TERT):c.3039C>T(p.His1013=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,092 control chromosomes in the GnomAD database, including 12,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (935 hom., cov: 33)
  • Exomes 𝑓: 0.11 (11110 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.189

Genes affected

TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-1255405-G-A is Benign according to our data. Variant chr5-1255405-G-A is described in ClinVar as [Benign]. Clinvar id is 39119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1255405-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.189 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.3039C>T	p.His1013=	synonymous_variant	14/16	ENST00000310581.10
TERT	NM_001193376.3	c.2850C>T	p.His950=	synonymous_variant	13/15
TERT	NR_149162.3	n.2747C>T		non_coding_transcript_exon_variant	11/13
TERT	NR_149163.3	n.2711C>T		non_coding_transcript_exon_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.3039C>T	p.His1013=	synonymous_variant	14/16	1	NM_198253.3	P2
	ENST00000666708.1	n.448G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0940 AC: 14308 AN: 152206 Hom.: 935 Cov.: 33

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.130 AC: 32473 AN: 249236 Hom.: 2681 AF XY: 0.129 AC XY: 17461 AN XY: 135332

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.0944

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.115 AC: 167415 AN: 1461766 Hom.: 11110 Cov.: 33 AF XY: 0.116 AC XY: 84287 AN XY: 727178

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.253

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.0935

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0939 AC: 14300 AN: 152326 Hom.: 935 Cov.: 33 AF XY: 0.0976 AC XY: 7270 AN XY: 74488

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.0967

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0939 Hom.: 496

Bravo AF: 0.0975

Asia WGS AF: 0.160 AC: 555 AN: 3478

EpiCase AF: 0.0999

EpiControl AF: 0.104

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	His1013His in exon 14 of TERT: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.1% (862/8526) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs33954691). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Aplastic anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2014

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dyskeratosis congenita, autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Dyskeratosis congenita, autosomal dominant 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	4.2
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs33954691; hg19: chr5-1255520; COSMIC: COSV57196876;